3-Methylamino-1-(2-thienyl)-1-propanone, production and use thereof

ABSTRACT

The present invention relates to the preparation of 3-methylamino-1-(2-thienyl)-1-propanone and its use for preparing the pharmaceutical (+)-(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine oxalate—(trade name Duloxetine®).

The present invention relates to the preparation and use of3-methylamino-1-(2-thienyl)-1-propanone.

The amino alcohol 1 (FIG. 1)[(1S)-3-methylamino-1-(2-thienyl)propan-1-ol] is a sought-afterintermediate in the preparation of a pharmaceutical((+)-(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamineoxalate—trade name Duloxetine®). The method which has been used thus farfor preparing this intermediate is elaborate and requires expensive andlabile reagents. Furthermore, a technically elaborate chromatography isrequired for preparing a pure compound. See, for example, EP 273658 A1;Liu et.al., Chirality 2000, 12 (1), 26-29; Wheeler et. al, J. LabelledComp. Radiopharm. 1995, 36(3), 213-23; U.S. Pat. No. 5,362,886, EP457559, Deeter et al , Tet. Lett. 1990, 31(49), 7101-4; EP 0650965; L.A. Sorbera, R. M. Castaner, J. Castaner, Drugs of the Future 2000,25(9): 907-916.

The object therefore was to make available simpler and more economicalprocesses for preparing Duloxetine®.

The present invention describes novel and economical processes forobtaining the isomerically pure compound 1. As an intermediate whichthey share in common, the processes according to the invention use thenovel ketone 5 (FIG. 1) [3-methylamino-1-(2-thienyl)-1-propanone], fromwhich the amino alcohol 1 can be obtained by means of enantioselectivereduction. The subsequent reaction of the aminoalcohol 1 to giveDuloxetine® is well known to the skilled person and can be carried outin analogy with the process described in EP 0457559 A2 (reaction with1-fluoronaphthalene).

The invention relates to 3-methylamino-1-(2-thienyl)-1-propanone (FIG.1, compound 5) and its acid addition salts. The acid addition salts ofcompound 5 are products of the reaction of compound 5 with inorganic ororganic acids. Acids which are particularly suitable for this purposeare hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid,fumaric acid, maleic acid and acetic acid.

The starting compound for preparing the ketone 5 or the amino alcohol 1can be thiophene or 2-acetylthiophene. FIG. 1 depicts three routes forpreparing the ketone 5 (routes 1 to 3), which routes are describedbelow:

Route 1

Compound 4 is obtained by way of a classical Mannich reaction startingwith acetylthiophene, formaldehyde and dimethylamine (EP 0457559 A2Example 1). The monomethylamino ketone 5 is obtained by means of aretromichael/Michael reaction, by reacting 4 with an excess ofmethylamine.

Route 2

Compound 6 is obtained by means of a classical Mannich reaction startingwith acetylthiophene, formaldehyde and methylamine (Blicke; Burckhalter;JACSAT; J. Amer. Chem. Soc.; 64; 1942; 451, 453). The monomethylaminoketone 5 is obtained by means of a retromichael/Michael reaction, byreacting 6 with an excess of methylamine.

Route 3

The compound 7 is obtained by means of a classical Friedel-craftsacylation of thiophene 8 with 3-chloropropionyl chloride (described inEl-Khagawa, Ahmed M.; El-Zohry, Maher F.; Ismail, Mohamed T.; PREEDF;Phosphorus Sulfur; EN; 33; 1987; 25-32). The monomethylamino ketone 5 isobtained by reaction with methylamine.

The invention also relates to the use of3-methylamino-1-(2-thienyl)-1-propanone or its acid addition salts forpreparing N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine, or itsacid addition salts, in racemic or enantiomerically pure form.Particular preference is given to the use for preparing(+)-(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine oxalate(Duloxetin®).

The invention also relates to a process for preparingN-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine, or its acidaddition salts, in racemic form or, preferably, in enantiomerically pureform, with 3-methylamino-1-(2-thienyl)-1-propanone or its acid additionsalts being prepared as intermediate in a first step with thisintermediate then being reduced to the corresponding alcohol.

The reduction can be carried out either under racemizing conditions orenantioselectively. Preference is given to an enantioselectivereduction, in particular to such a reduction which yields the(S)-enantiomer 1 as the product.

This can be carried out either chemically, using classicalenantioselective hydrogenation methods,. such as using NaBH₄ or LiAlH₄,which are provided with chiral ligands for the purpose of achievingenantioselectivity, or using transition metal-containing hydrogenationcatalysts or using enzymic reductions, for example using microbial, inparticular bacterial or fungal, dehydrogenases.

Experimental:

Route 1:

5 g of dimethylamino ketone 4 are initially introduced as thehydrochloride in 25 ml of ethanol after which 20 eq. of methylamine (40%in water) are added dropwise and the mixture is stirred at 60-70° C. for6 h. After the reaction has come to an end, part of the ethanol isremoved and the product 5 is obtained as a white crystalline solid(yield, 3.45 g as the hydrochloride).

Route 2:

5 g of diketone 6 are initially introduced, as the hydrochloride, in 25ml of ethanol after which 20 eq. of methylamine (40% in water) are addeddropwise and the mixture is stirred at 70-80° C. for 6 h. After thereaction has come to an end, part of the ethanol is removed and theproduct 5 is obtained as a white crystalline solid (yield, 3.87 g as thehydrochloride).

Route 3:

5 g of chloroketone 7 are initially introduced in 25 ml of THF afterwhich 20 eq. of methylamine (40% in water) are added dropwise and themixture is stirred at 30-40°C. for 6 h. After the reaction has come toan end, most of the THF is removed and the product 5 is isolated as awhite crystalline solid (yield, 4.10 g as the hydrochloride).

In routes 1-3, aqueous methylamine can also be replaced with gaseous orliquefied methylamine.

Spectroscopic data for the monomethylamino ketone 5 as thehydrochloride:

¹³C NMR (D₂O, 125 MHz) spin-echo multiplicities in brackets: δ(ppm)=188.5 (s), 140.4 (s), 139.2 (d), 137.8 (d), 131.9 (d), 46.9 (t),37.3 (t), 36.0 (q) ¹H NMR (D₂O, 500 MHz): δ (ppm)=8.00 (m, 1H), 7.95 (m,1H), 7.25 (m, 1H), 3.40 (m,2H), 2.75 (m, 2H), 2.62 (s, 3H)

Reduction of compound 5 to give compound 1 (FIG. 1)

NaBH4 (racemic):

5 g of methylamino ketone 5 were initially introduced in 20 ml ofethanol after which 0.8 eq. of NaBH4 was added in portions at 20° C.After the mixture had been stirred for 6 h, it was subjected to aqueousworkup. The racemic monomethylaminoalcohol 1 was obtained as a paleyellow solid (yield: 3.9 g)

1H NMR (500 MHz, CDCl3) δ(ppm)=2.1 (m, 2H), 2.5 (s, 3H), 2.9 (m, 2H),4.5 (br s, 2H), 5.25 (m, 1H), 6.94 (m, 1H), 7.00 (m, 1H), 7.22 (m,1H)13C NMR (125 MHz, CDCl3) δ (ppm)=35.4, 36.3, 49.7, 71.4, 122.5, 123.8,126.6, 149.3

LiAlH4 (chirally modified) carried out as in EP 0457559 A2, example 1B(enantioselectively).

The yield of 1 was 74%, with an enantiomeric purity of 72% ee.

1. 3-Methylamino-1-(2-thienyl)-1-propanone, and its acid addition salts.2. 3-Methylamino-1-(2-thienyl)-1-propanone hydrochloride.
 3. (canceled)4. (canceled)
 5. (canceled)
 6. A process for preparing(+)-(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine oxalate(Duloxetin®), wherein 3-methylamino-1-(2-thienyl)-1-propanone, or anacid addition salt thereof, is prepared as intermediate.
 7. The processaccording to claim 6, wherein 3-methylamino-1-(2-thienyl)-1-propanone,or an acid addition salt thereof, is reduced to(1S)-3-methylamino-1-(2-thienyl)propan-1-ol, or an acid addition saltthereof.
 8. The process according to claim 7, wherein the reduction iscarried out using a microbial dehydrogenase.
 9. A process for preparingN-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine or its acid additionsalts which comprises using said3-Methylamino-1-(2-thienyl)-1-propanone, and its acid addition salts asclaimed in claim 1.